Summary Nearly half of all pregnancies in the U.S. are unintended, and most occur in women who are not using contraceptives. There are diverse reasons for not using contraceptives; one common reason is that many women have a strong aversion to using exogenous hormones due to real and perceived side effects. It is likely that contraceptive use and satisfaction would substantially increas if there is a non-hormonal, user-controlled contraceptive method that does not require coitally-timed actions nor daily dosing. Such product does not currently exist. We believe we can create such a non-hormonal contraceptive based on an intravaginal ring (IVR) releasing a sperm-binding antibody (Ab) that agglutinates and traps sperm in mucus, thereby preventing sperm from reaching the egg. Topical passive immunization by direct delivery of anti-sperm Ab to the vagina was validated in animal models in the 1980s-1990s, and directly overcomes the variable intensity and uncertain reversibility of contraceptive vaccines. However, this strategy was not practical until recently due to the high costs of Ab production. Given the remarkable advances in bioprocessing that have greatly reduced the manufacturing costs of Ab, we believe the time is now ripe to develop an IVR for sustained passive immunization of the vagina with a potent anti-sperm Ab. Our approach is based on a well characterized and validated antigen target present on human sperm, and we have a fully human mAb that binds this antigen and agglutinates within seconds all human sperm, and does so in over 100 semen samples from diverse semen donors. We further increased sperm-agglutination potency by engineering novel high- valency constructs comprising six Fab domains (i.e. 4 additional Fabs linked to the parent IgG molecule) and eight Fab domains (6 additional Fabs); we term these constructs MM006 and MM007, respectively. In addition, we enhanced the safety profile by incorporating Fc mutations that reduce binding to FcgR, mitigating the likelihood of developing immunity against sperm. By incorporating multiple Fab domains while preserving Fc, we substantially improved agglutination speed and potency, while retaining the stability and ease of commercial manufacturing of parent IgG. Since the antigen target is present only on human sperm, this precludes direct evaluation of contraceptive efficacy in animals. Instead, our goal in the R61 phase is to select between MM006 and MM007, formulate the mAb into a capsule-IVR, and demonstrate the IVR can sustain effective contraceptive concentrations and assess local distribution and toxicity in the sheep vagina model, which is anatomically similar to the human vagina. If we meet the R61 milestones, we will focus the R33 phase on developing cGMP-compliant manufacturing process for the selected mAb, culminating in Master Cell Banked CHO cells (essential part of IND filing) and GLP tox study in rats. If successful, the work will strongly support clinical evaluation of our non-hormonal contraceptive IVR that could address a significant unmet need in the marketplace, and lay the foundation for multifuntional IVRs that also protects against STIs.